1. Field of the Invention
The present invention is directed to new cephem derivatives represented by the general formula ##STR3## in which the Acyl substituent is a group of the formula ##STR4## where Ar is an optionally substituted lipophilic phenyl, naphthyl, pyridyl or benzthiazolyl group, R.sup.1 is selected from certain optionally substituted aliphatic, aromatic, arylaliphatic or sugar moieties and R.sup.2 and R.sup.3 are each independently hydrogen, alkyl or aminoalkylcarbonylamino. The derivatives are gram-positive antibacterial agents, especially useful in the treatment of diseases caused by methicillin-resistant Staphylococcus aureus (also referred to below as MRSA or methicillin-resistant S. aureus).
2. Description of the Prior Art
The literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents. Applicants are not aware, however, of any literature disclosing compounds with the combination of C-3 and C-7 substituents found by applicants to give good activity against MRSA organisms. There are, however, references which disclose cephalosporins having the type of 7-substituents or the type of 3-substituents present in the compounds claimed in the present application.
For example, there are references which disclose applicants' C-7 substituents. Among such references disclosing 7-substituents of the type ##STR5## where Ar is an aromatic group are the following:
U.S. Pat. No. 4,056,676 discloses cephem derivatives of the general formula ##STR6## where Z is hydrogen or fluorine; and when Z is hydrogen, each of X and Y is hydrogen or chlorine selected so that the phenyl ring is substituted with 1 or 2 chlorine atoms and so that when one chlorine atom is present said chlorine atom is in the 3-position, and when two chlorine atoms are present said chlorine atoms are in the 3,4-, the 3,5- or the 2,5-positions; and when Z is fluorine, said fluorine is in the 3- or 4-positions of the phenyl ring and each of X and Y is hydrogen or chlorine selected so that when the phenyl ring is substituted with 1 or 2 chlorine atoms, one of the chlorine atoms is in the 3- or 4-position of the phenyl ring; R.sup.1 is hydrogen, dicyclohexylamine, or a pharmaceutically acceptable cation; and R is, inter alia, N-pyridino. Among the compounds specifically disclosed are those of the formulae: ##STR7## The compounds disclosed are said to be useful for treating and inhibiting the growth of MRSA organisms.
The cephalosporin derivative of the formula ##STR8## is disclosed in Antimicrobial Agents and Chemotherapy--1966, pg. 573-580 at page 576 (Compound No. 48).
J. Antibiotics, 26(12), 737-744, 1973, discloses the compound of the formula ##STR9##
U.K. Patent 998,265 discloses cephem derivatives of the general formula ##STR10## in which R.sup.1, taken alone, is --OH, C.sub.1 -C.sub.8 acyloxy, or tertiaryamino, R.sup.2 is --OH when R.sup.1 is --OH, R.sup.2 is --OH when R.sup.1 is C.sub.1 -C.sub.8 acyloxy, R.sup.2 is --O-- when R.sup.1 is tertiaryamino, R.sup.1 and R.sup.2, when taken together, are --O--, R.sup.3 and R.sup.4 represent hydrogen, alkyl radicals having from 1 to 6 carbon atoms, alkenyl radicals having from 2 to 6 carbon atoms, cycloalkyl radicals having from 5 to 7 carbon atoms, or alkoxyalkyl radicals having from 2 to 6 carbon atoms; n represents 0 to 4; and R.sup.5 represents an alkyl radical having from 1 to 6 carbon atoms, an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, a cycloalkyl radical having 5 or 6 carbon atoms, phenyl, .beta.-furyl, .beta.-thienyl, thienyl, or naphthyl, or a fluoro, chloro, bromo, nitro, trifluoromethyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkylmercapto, or C.sub.1 -C.sub.4 alkoxy substitution product of such radicals.
U.K. Published Application No. 2,007,221 A discloses cephalosporin derivatives of the formula ##STR11## wherein Y is hydrogen, chlorine, bromine, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; Z is a bond, oxygen or sulfur; W is hydrogen, methyl, amino, hydroxy, SO.sub.3 H or COOR.sub.4 wherein R.sub.4 is hydrogen or 5-indanyl with the proviso that when Z is oxygen or sulfur, W is other than hydroxy; R.sub.1 is hydrogen or methoxy; R.sub.2 is hydrogen, acetoxy, 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4-oxadiazol-2-ylthiol, 1,3,4-triazol-2-ylthio, 5-methyl-1,3,4-triazol-2-ylthio, 1,2,3-triazol-5-ylthio, pyridinium or 4-aminocarbonylpyridinium; R.sup.3 is hydrogen, a negative charge when R.sup.2 is pyridinium or 4-aminocarbonylpyridinium, a cation of an alkali metal or an alkaline earth metal, ammonium or organic ammonia cations, C.sub.1 -C.sub.4 alkyl, (C.sub.2 -C.sub.5 alkanoyloxy)methyl, (C.sub.2 -C.sub.5) alkanoylamino)methyl, [C.sub.2 -C.sub.5 alkanoyl(C.sub.1 -C.sub.4 alkoxy)carbonyl(C.sub.1 -C.sub.4 alkyl)-amino-methyl, p-(C.sub.2 -alkanoyloxy)benzylamino(C.sub.2 -C.sub.15 alkanoyloxy)methyl, (C.sub.1 -C.sub.4 alkyl)amino(C.sub.2 -C.sub.15 alkanoyloxy)methyl or di(C.sub.1 -C.sub.4 alkyl)amino(C.sub.2 -C.sub.15 alkanoyloxy)methyl; and pharmaceutically acceptable salts thereof.
U.S. Pat. No. 3,217,000 discloses cephem derivatives of the formula ##STR12## wherein Thi is 2-thienyl or 3-thienyl and R is a substituent at the 3 or 4 position of the pyridino ring selected from the group consisting of cyano, carboxy, carbamyl, N-methylcarbamyl, carbo(C.sub.1 -C.sub.4 alkoxy), hydroxy and (C.sub.1 -C.sub.4)alkanoyl; and the salts thereof with pharmaceutically acceptable acids.
There is also literature disclosing cephalosporins having 3-substituents of the type ##STR13## where R is an optionally substituted aliphatic or aromatic group. Among such references are those of the following:
U.S. Pat. No. 4,758,557 discloses cephalosporin derivatives of the general formula ##STR14## wherein A represents an alkanoyloxy group having 2-5 carbon atoms; a carbamoyloxy group; an azido group; or an unsubstituted or substituted pyridylthio group of the formula ##STR15## where n is 0 or an integer of 3-5; R.sup.1 and R.sup.2 may be the same or different and each represents a hydrogen atom, a halogen atom, a carboxyl group or an optionally halogen-substituted lower-alkyl group having 1-5 carbon atoms; or an unsubstituted or substituted pyridiniumthio group of the formula ##STR16## where n, R.sup.1 and R.sup.2 have the same meanings as above; R.sup.3 represents a linear or branched-chain alkyl group having 1-5 carbon atoms, a halogen-substituted alkyl group, a cyclopropyl group, a cyclopropylmethyl group, an alkenyl group, an oxygen atom or a group of (--CH.sub.2).sub.m -B where m is an integer of 0-3 and B represents a hydroxyl group, an alkoxy group, an amino group, an alkyl-substituted amino group, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a hydroxamic group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylaminocarbonyl group or an acetamidosulfonyl group; or an unsubstituted or substituted pyridinium group of the formula ##STR17## where n has the same meaning as above; R.sup.4 and R.sup.5 may be the same or different and each represent a hydrogen atom, a linear or branched alkyl group having 1-5 carbon atoms, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a linear or branched alkylthio group having 1-5 carbon atoms, a halogen-substituted alkylthio group, a cycloalkanothio group, a carbamoylalkylthio group, an alkoxyalkylthio group or an alkyl-substituted aminoalkylthio group; or a 5- or 6-membered heterocyclicthio or bicycloheterocyclicthio group of the formula EQU --S--Het
wherein Het represents an optionally substituted thiazole, isothiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,3,4-tetrazole, pyrimidine, 1,2,4-triazine, benzothiazole, benzimidazole, benzoxazole, 1,3,4-triazaindolidine or 2,3-dihydro-1H-indolidinium group.
Illustrative of the compounds encompassed by U.S. Pat. No. 4,758,557 is MT0703 having the structure ##STR18## which is disclosed in J. Antibiotics 43(2), 189-198, 1990.
U.S. Pat. No. 4,786,633 discloses cephalosporin derivatives of the formula ##STR19## wherein R.sup.2 is a substituted or unsubstituted heterocyclic group having 1-3 hereto atoms selected from the group consisting of nitrogen and sulfur. The R.sup.2 group may be, for example, a group of the formula ##STR20## where R.sup.4 is lower alkenyl, lower alkyl, or a lower alkyl group substituted with a carbamoyl group and R.sup.5 and R.sup.6 are the same or different and each represent hydrogen or lower alkyl.
Published European Patent Application 409,164 A2 discloses cephalosporin derivatives of the formula ##STR21## wherein R.sup.1 is an amino group or acylamino; R.sup.2 is hydrogen or methoxy; R.sup.3 is hydrogen or a mono- or divalent substituent; R.sup.4 is optionally protected vic-dihydroxyaryl; R.sup.5 is straight or branched lower alkylene; R.sup.6 is hydrogen, a carboxy-protecting group or a negative charge when combined with Y; X is oxygen, sulfur, or sulfinyl; and Y is an anion or a negative charge when combined with R.sup.6; and the dotted line shows the presence or absence of a bond.